Abstract Background Prognostic markers of response to tofacitinib (TFB) are lacking in ulcerative colitis (UC). Multidrug resistance protein (MDR) activity, alterations in metabolism via cytochrome-P450 (CYP) isoenzymes, mucosal change of JAK/STAT signalling pathways may predict treatment response. Methods We enrolled adult UC patients before introducing TFB treatment and followed them until w12. At baseline we measured the activity of three ABC drug transporters (MDR1, MRP1, and BCRP) in leukocytes. Patients’ tofacitinib-metabolizing capacity was characterized by CYP2C19, CYP3A5 and CYP3A4 genotypes. Clinical parameters were registered, while colonoscopy examinations were performed at baseline and at w12. Mucosal sampling was also performed to measure mucosal cytokine levels (e.g. TNF-α, PAI-1) and alterations in JAK/STAT gene expressions. W12 corticosteroid-free remission (CSFR) and endoscopic remission/response, histological remission (HR) and treatment persistence were used as outcomes. We performed multivariable logistic regression models on these specific outcomes and data was handled with intention-to-treat analysis. Results In total, we included 63 patients (male/female ratio 24/39; mean age 38.7±11.7 years; mean Mayo score 8.9±2.4) in our study. In total, 7 patients (9.2%) achieved HR, while 20 patients (26.7%) achieved endoscopic remission, and 27 patients (42.9%) endoscopic response. Clinical remission was observed in 21 patients (33.3%), while clinical response was achieved by 30 patients (47.6%). In total, 34 patients (54.0%) were in CSFR at w12, and higher baseline pMayo score decreased (OR = 0.64 95% CI:0.43–0.94), while albumin increased (OR = 1.33 95% CI:1.01–1.76) the chance of achieving the outcome (AUC = 0.93). We found that one-year treatment persistence was strongly influenced by week 12 endoscopic remission (β = 3.79 95% CI:1.21–6.37), but not by histological remission (β = 1.58 95% CI:-0.74–3.89). Higher baseline CD8⁺ MDR1 activity decreased the chance of clinical response (OR = 0.91; p = 0.048), while higher CD8⁺ MRP1 decreased week 12 treatment persistence (r = 0.32). CYP3A5 1/3 genotype increased the histological remission rates (OR = 13.9 95% CI:1.04-186.2). The levels of mucosal IL-6 (18.51 vs 25.72 pg/mg, p = 0.049), IL-4 (94.41 vs 168.8 pg/mg, p = 0.037) and PAI-1 (921 vs 1483 pg/mg, p = 0.01) were significantly lower in the clinical/endoscopic responders at the baseline. Conclusion Based on our prospective cohort study, short-term histological remission is still a hard-to-reach endpoint in moderate-to-severe UC on TOFA. Measurement of baseline CD8⁺ MRP1 and CD8⁺ MDR1 activity, and mucosal levels of IL-1β, IL-6, IL-4, and PAI-1, and CYP3A5 genotype may help to increase treatment success. Conflict of interest: Dr. Resál, Tamás: Jójárt, Boldizsár: I have no conflict of interest. Bacsur, Péter: No conflict of interest Kajári, Lilian: No conflict of interest Molnár, Tünde: No conflict of interest Balázs, Hallgas: No conflict of interest Tímea, Pintér: No conflict of interest Kovács, Blanka: No conflict of interest Éva, Kárpáti: No conflict of interest Katalin, Monostory: No conflict of interest Farkas, Bernadett: No conflict of interest Ivány, Emese: No conflict of interest Bálint, Anita: No conflict of interest Fábián, Anna: No conflict of interest Bor, Renáta: No conflict of interest Rutka, Mariann: No conflict of interest Szepes, Zoltán: No conflict of interest Farkas, Klaudia: No conflict of interest József, Maléth: No conflict of interest Molnár, Tamás: No conflict of interest
Resál et al. (Thu,) studied this question.